Phenotypic Discovery of Neuroprotective Agents by Regulation of Tau Proteostasis via Stress‐Responsive Activation of PERK Signaling,Angewandte Chemie International Edition

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Phenotypic Discovery of Neuroprotective Agents by Regulation of Tau Proteostasis via Stress‐Responsive Activation of PERK Signaling
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2020-11-18 , DOI: 10.1002/anie.202013915
Young‐Hee Shin ₁ , Hana Cho ₂ , Bo Young Choi ₃ , Jonghoon Kim _{1,

4} , Jaeyoung Ha ₂ , Sang Won Suh ₃ , Seung Bum Park _{1,

2}

Affiliation

Tau protein aggregates are a recognized neuropathological feature in Alzheimer's disease as well as many other neurodegenerative disorders, known as tauopathies. The development of tau‐targeting therapies is therefore extremely important but efficient strategies or protein targets are still unclear. Here, we performed a cell‐based phenotypic screening under endoplasmic reticulum (ER) stress conditions and identified a small molecule, SB1617, capable of suppressing abnormal tau protein aggregation. By applying label‐free target identification technology, we revealed that the transient enhancement of protein kinase‐like endoplasmic reticulum kinase (PERK) signaling pathway through the inhibition of stress‐responsive SB1617 targets, PDIA3 and DNAJC3, is an effective strategy for regulating proteostasis in tauopathies. The molecular mechanism and the promising efficacy of SB1617 were demonstrated in neuronal cells and a mouse model with traumatic brain injury, a tauopathy known to involve ER stress.

中文翻译：

通过保护应激反应激活PERK信号传导调节Tau蛋白稳态来表型性地发现神经保护剂。

Tau蛋白聚集体是阿尔茨海默氏病以及许多其他神经退行性疾病（称为tauopathies）的公认神经病理学特征。因此，靶向tau疗法的发展极为重要，但尚不清楚有效的策略或蛋白质靶标。在这里，我们在内质网（ER）胁迫条件下进行了基于细胞的表型筛选，并鉴定了能够抑制tau蛋白异常聚集的小分子SB1617。通过应用无标记的靶标识别技术，我们揭示了通过抑制应激反应性SB1617靶标PDIA3和DNAJC3来瞬时增强蛋白激酶样内质网激酶（PERK）信号通路是一种有效的调控蛋白水解的策略。 tauopathies。

更新日期：2021-01-18

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